Current Immunotherapeutic Strategies in Cancer

190 Pages·2020·2.497 MB·English

by  Matthias Theobald

Recent Results in Cancer Research
Series Editors: Peter-Michael Schlag · Hans-Jörg Senn
Matthias Theobald Editor
Current
Immunotherapeutic
Strategies in Cancer
Recent Results in Cancer Research
Volume 214
Series Editors
Peter-Michael Schlag, Charite Campus Mitte, Charite Comprehensive Cancer
Center, Berlin, Germany
Hans-Jörg Senn, Tumor- und Brustzentrum ZeTuP, St. Gallen, Switzerland
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Matthias Theobald
Editor
Current
Immunotherapeutic
Strategies in Cancer
123
Editor
Matthias Theobald
Department ofHematology, Oncology
andPneumology, University Cancer
Center(UCT) Mainz
JohannesGutenberg University
Medical Center
Mainz,Germany
ISSN 0080-0015 ISSN 2197-6767 (electronic)
Recent Resultsin Cancer Research
ISBN978-3-030-23764-6 ISBN978-3-030-23765-3 (eBook)
https://doi.org/10.1007/978-3-030-23765-3
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Contents
Current Development of Monoclonal Antibodies
in Cancer Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Sagun Parakh, Dylan King, Hui K. Gan and Andrew M. Scott
Clinical Experience with Bispecific T Cell Engagers . . . . . . . . . . . . . . . 71
Nicola Gökbuget
Advances and Challenges of CAR T Cells in Clinical Trials . . . . . . . . . 93
Astrid Holzinger and Hinrich Abken
Targeting Cancer with Genetically Engineered TCR T Cells. . . . . . . . . 129
Thomas W. Smith Jr. and Michael I. Nishimura
Personalized Neo-Epitope Vaccines for Cancer Treatment. . . . . . . . . . . 153
Mathias Vormehr, Mustafa Diken, Özlem Türeci, Ugur Sahin
and Sebastian Kreiter
The Era of Checkpoint Inhibition: Lessons Learned
from Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Annette Paschen and Dirk Schadendorf
v
Current Development of Monoclonal
Antibodies in Cancer Therapy
Sagun Parakh, Dylan King, Hui K. Gan and Andrew M. Scott
1 Antibody Structure
Antibodies are the epitome of specificity with an estimated ten billion different
antibodies produced by human B cells; there is an extraordinarily diverse range of
antibodiescapableofbeingproducedbytheimmunesystem(Fanningetal.1996).
Antibodies are made up offour polypeptide chains, two identical light chains and
two identical heavy chains, which are joined by disulphide bridges forming a
structure that is similar to the shape of a Y (Fig. 1) (Merino 2011). Both the light
and heavy chains are comprised of variable and constant domains, each with dif-
feringfunctions(Merino2011).Thevariabledomainsdetermineantigenspecificity,
and the constant domains determine immunoglobulin (Ig) class. For the light
chains,theconstantdomaindiffersdependingonwhethertheyareencodedbyjor
k genes (Merino 2011). Similarly, the constant domain of the heavy chain varies
with5genes(c,µ,a,dande),andthisdeterminestheoverallantibodyclass(IgG,
IgM, IgA, IgD and IgE, respectively) (Merino 2011). Furthermore, IgA has two
S.Parakh(cid:1)D.King(cid:1)H.K.Gan(cid:1)A.M.Scott(&)
TumourTargetingLaboratory,OliviaNewton-JohnCancerResearchInstitute,
145StudleyRoad,Heidelberg,Melbourne,VIC3084,Australia
e-mail:[email protected]
S.Parakh(cid:1)H.K.Gan
DepartmentofMedicalOncology,OliviaNewton-JohnCancerandWellnessCentre,
AustinHealth,Heidelberg,Melbourne,Australia
S.Parakh(cid:1)D.King(cid:1)H.K.Gan(cid:1)A.M.Scott
SchoolofCancerMedicine,LaTrobeUniversity,Melbourne,Australia
DepartmentofMolecularImagingandTherapy,AustinHealth,Melbourne,Australia
DepartmentofMedicine,UniversityofMelbourne,Melbourne,Australia
©SpringerNatureSwitzerlandAG2020 1
M.Theobald(ed.),CurrentImmunotherapeuticStrategiesinCancer,
RecentResultsinCancerResearch214,
https://doi.org/10.1007/978-3-030-23765-3_1
2 S.Parakhetal.
Fig.1 Antibody structure: Antibodies are made up offour polypeptide chains, two identical
lightchainsandtwoidenticalheavychains,joinedbydisulphidebridges.Heavychainscomprise
one variable (V ) domain followed by a constant domain (C 1), a hinge region and two more
H H
constant (C 2 and C 3) domains. The light chain has one variable (V ) and one constant (C )
H H L L
domain. Thetwoarms in theY-shapedstructure containtheantigen-binding sites, thefragment
antigen-binding (Fab) region,along with the base of theY-shaped structure called the fragment
crystallizable (Fc) region. Antigen specificity in the Fab region is determined by
complementarity-determiningregions(CDRs)withinthevariabledomains
subclasses, IgA1 and IgA2, and IgG, four: IgG1, IgG2, IgG3 and IgG4 (Merino
2011). In healthy people, IgG antibodies represent approximately 75% of serum
antibodies, 15% are IgA, 10% are IgM, along with very small amounts of circu-
latingIgDandIgEantibodies.IgGantibodiesaretheprimaryisotypeusedincancer
therapy and as such will be the major focus in the following sections.
Functionally,antibodiesaredividedintotwoparts;thetwoarmsintheY-shaped
structure contain the antigen-binding sites and are named as the fragment
antigen-binding (Fab) region, along with the base of the Y-shaped structure which
mediates immunological signalling by antibodies and is called the fragment crys-
tallizable(Fc)region.TheFabarmofanIgGantibodycontainsthefulllightchains
and part of the heavy chain, each with their own constant and variable domains.
Antigen specificity in the Fab region is determined by complementarity-
determining regions (CDRs) within the variable domains. These CDRs have the
greatest sequence variation within antibodies, and this feature gives rise to the
CurrentDevelopmentofMonoclonalAntibodiesinCancerTherapy 3
diverse range of antigen specificities. There are three CDRs for each variable
region, which means six CDRs (heavy and light) for each Fab arm and twelve in
totalforasingleantibodymolecule.ThesixCDRsoneachFabarmfoldtogetherto
form the antigen-binding pocket, and this allows an antibody to be able to simul-
taneously bind two epitopes. When antibodies recognize a soluble antigen, this
simultaneous binding can produce large multimeric structures called immune
complexes.
Within the immune system, a principle function of antibodies is to neutralize
pathogenssuchasbacteriaandviruses.TheCDRswithinthevariableregionsofan
antibody recognize a specific molecular structure of an antigen, called the epitope,
present on the pathogen. Because of the random nature of antibody generation in
thedevelopmentofeachindividualBcell,therearemillionsofBcellscirculatingat
anygiventimethateachrecognizeadifferentantigen.OnceaBcellencountersan
invadingpathogenwithitsuniqueepitope,itundergoesmaturationwiththehelpof
specific T cells and produces large amounts of soluble antibody. Multiple B cells
will recognize different epitopes present on the pathogen, and so many different
antibodieswillbeproduced.Onceproduced,theseantibodiesbindtheirantigenon
the surface of the bacteria or virus to neutralize the pathogen and mark it for
destruction by innate immune effector cells.
1.1 Target Antigens
Following the discovery of antibodies and their functions, it was realized that they
would be potentially efficacious for the treatment and diagnosis of cancers (Rettig
andOld1989;Scottetal.2012).Becauseantibodiesareuniquelyspecificfortheir
targetantigen,theycouldbeusedtodirectlytargettumoursexpressingtheantigen.
For ideal targeting of tumour-associated antigens (TAA), what is required is a cell
surface antigen on the tumour that is mutated, overexpressed or selectively
expressed when compared to normal tissue (Scott et al. 2012). Ideally, the target
antigenwouldbehomogenouslyexpressedwithinthetumourandantigensecretion
would be minimal, in order to reduce antibody trapping in the circulation (Scott
et al. 2012). In addition to expression, antigen function and effect on downstream
signalling are also taken into consideration when selecting a target.
TAAs that are targeted by therapeutic antibodies can be initially grouped on
what type of cancer they target (Tables 1 and 2). Haematological cancers are
usuallytargetedthroughclusterofdifferentiation(CD)antigensthatincludeCD20,
CD30, CD33 and CD52 (Scottetal.2012), whereas solid tumours can be targeted
through a variety of antigens that fall into different categories based on their
function. The epidermal growth factor receptor (EGFR) is one such example of a
TAA that has been successfully targeted in cancer therapy (Scott et al. 2012).
Antibodies that target EGFR abrogate the native function of the receptor, thereby
inhibiting tumour growth, and can also recruit innate immune cells through
Fc-signalling to mediate killing of the tumour.
4 S.Parakhetal.
OS25.1versusp20.3months=0.046 OS75%versusp84%;<0.001 OS13.8versusp11.1months;=0.046 OS56.5versusp40.8months;=0.0002 OS30.9versusp25.1months;<0.001 (continued)
PFS7.4versus4.6pmonths;<0.001 PFS6.7versus5.5pmonths;=0.002 PFS18.7versusp12.4months;<0.0001 DFS 81% 86% 73% 73% PFS9.6versus6.4Pmonths;<0.001
Endpoints ORR50%versusp32%;<0.001 DFS62%versusp74%;<0.001 ORR47%versus35% pCR 29% 46% 17% 24% ORR44%versusP31%;<0.001
b
Treatmentarms Chemotherapy+trastuzumabversuschemotherapy ±TACtrastuzuma ±Chemotherapytrastuzumab Trastuzumab+±docetaxelpertuzumab T+D P+T+D P+T P+D T-DM1versuscapecitabine+lapatinib
Trial Slamonetal.(2001) NSABPB31+N9831(Perezetal.2011,2014) TOGA(Bangetal.2010) CLEOPATRA(Swainetal.2015) NEOSPHERE(Giannietal.2012) EMILIA(Vermaetal.2012)
s Year 1997 2006 2010 2012 2012 2013
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oclonalantibodi Indication Metastaticbreastcancer Node-positivebreastcancer MetastaticgastricorGEJadenocarcinoma Metastaticbreastcancer Breastcancer Metastaticbreastcancer
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b b
Approved Drug Trastuzuma Pertuzumab Trastuzumaemtansine(T-DM1)
1
Table Target HER2